EP2190534B1 - Derivatives of 5-amino-4, 6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators - Google Patents

Derivatives of 5-amino-4, 6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators Download PDF

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Publication number
EP2190534B1
EP2190534B1 EP08827266.1A EP08827266A EP2190534B1 EP 2190534 B1 EP2190534 B1 EP 2190534B1 EP 08827266 A EP08827266 A EP 08827266A EP 2190534 B1 EP2190534 B1 EP 2190534B1
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EP
European Patent Office
Prior art keywords
dimethyl
compound
formula
dimethylbutanamide
pharmaceutically acceptable
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EP08827266.1A
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German (de)
English (en)
French (fr)
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EP2190534A1 (en
Inventor
Jean-Michel Vernier
Huanming Chen
Jianlan Song
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VALEANT PHARMACEUTICALS INTERNATIONAL Inc
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Valeant Pharmaceuticals International Inc USA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention concerns novel compounds that modulate potassium channels.
  • the compounds are useful for the treatment and prevention of diseases and disorders which are affected by activities of potassium ion channels.
  • One such condition is seizure disorders.
  • Epilepsy is a well-known neurological disease, found in about 3% of the population. Approximately 30% of patients with epilepsy do not respond to currently available therapies. Retigabine (N-[2-amino-4-(4-fluorobenzylamino) phenyl] carbamic acid, ethyl ester] (United States Patent No. 5,384,330 ) has been found to be an effective treatment of a broad range of models of seizure disorders, and it appears to have an unusual mechanism of action. Bialer, M. et al., Epilepsy Research 1999, 34, 1-41 ; Wuttke, T.V., et al., Mol. Pharmacol. 2005, 67, 1009-1017 ..
  • Retigabine has also been found to be useful in treating pain, including neuropathic pain. Blackburn-Munro and Jensen, Eur. J. Pharmacol. 2003,460, 109-116 ; Wickenden, A.D. et al., Expert Opin. Ther. Patents, 2004, 14(4 ).
  • Retigabine has been shown to increase the conductance of the channels at the resting membrane potential, with a possible mechanism involving binding of the activation gate of the KCNQ 2/3 channel. Wuttke, T.V., et al., Mol. Pharmacol. 2005 , op.cit. With increased sophistication of research in this area, retigabine has also been shown to increase neuronal M currents and to increase the channel open probability of KCNQ 2/3 channels. Delmas, P. and Brown, D.A. Nat. Revs Neurosci., vol. 6, 2005, 850-62 ; Tatulian, L. and Brown, D.A., J. Physiol., (2003) 549, 57-63 .
  • the most therapy-resistant type of seizure is the so-called "complex partial seizure.”
  • Retigabine has been found to be particularly potent in models for drug-refractory epilepsy.
  • Retigabine is also active in several other seizure models. Because of retigabine's broad spectrum of activity and unusual molecular mechanism, there is hope that retigabine will be effective in management of several seizure types, including the complex partial seizure, and in treatment of hitherto untreatable forms of epilepsy.
  • the present invention provides a compound which is one of the following:
  • the invention provides a composition comprising a pharmaceutically acceptable carrier and one or more of the following: at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof.
  • the invention provides the above composition for use in preventing or treating a disease or disorder which is affected by modulation of potassium channels.
  • a compound of formula I where the dashed line represents an optional double bond; where R 1 is pyrimidyl, pyrrolyl, imidazolyl, pyrazyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl, optionally substituted with one or two substituents selected independently from halogen, C 1 -C 6 alkyl, mono-halo C 1 -C 6 alkyl, di-halo C 1 -C 6 alkyl, CF 3 , CN, S-C 1 -C 6 alkyl, or O-C 1 -C 6 alkyl; R 2 is methyl, or halogen; R 3 and R 4 are, independently, CF 3 , OCF 3 , OC 1 -C 3 alkyl, halo or C 2 -C 3 alkyl, where the C 2 -C 3 alkyl groups are optionally substituted with one or more
  • this invention provides a composition
  • a pharmaceutically acceptable carrier and one or more of the following: a pharmaceutically effective amount of a compound of the present invention a pharmaceutically effective amount of a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a pharmaceutically acceptable ester thereof.
  • this invention provides or contemplates a composition
  • a composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of a compound of the present invention; ii) a pharmaceutically acceptable salt thereof; iii) a pharmaceutically acceptable ester thereof; iv) a pharmaceutically acceptable solvate thereof.
  • Also described is a method of treating or preventing a disease or disorder which is affected by enhancement of neural M currents comprising administering to a patient in need thereof one or more of the following: i) a pharmaceutically effective amount of a compound of the present invention; ii) a pharmaceutically acceptable salt thereof; iii) a pharmaceutically acceptable ester thereof; iv) and a pharmaceutically acceptable solvate thereof.
  • Also described is a method of treating or preventing a seizure disorder in a human comprising administering to a patient afflicted or potentially afflicted with such disorder one or more of the following: a pharmaceutically effective amount of a compound of the present invention; ii) a pharmaceutically acceptable salt thereof; iii) a pharmaceutically acceptable ester thereof; iv) and a pharmaceutically acceptable solvate thereof.
  • this invention provides or contemplates a pharmaceutical formulation for oral administration comprising a therapeutically effective amount of a compound of the present invention and either an appropriate tabletting agent or an appropriate syrup for pediatric use.
  • this invention provides or contemplates a tablet for oral administration comprising a therapeutically effective amount of a compound of the present invention and an appropriate tabletting agent.
  • this invention provides or contemplates a syrup for pediatric use comprising a solution or dispersion or suspension of a compound of the present invention and an appropriate syrup.
  • this invention contemplates a pharmaceutical formulation for administration to animals, including companion animals (dogs and cats), and livestock comprising a therapeutically effective amount of a compound of the present invention and a veterinary acceptable carrier.
  • Also described is a method of preventing or treating a disease or disorder which is affected by activation of voltage-gated potassium channels comprising administering to an animal in need thereof one or more of the following: i) a pharmaceutically effective amount of a compound of the present invention; ii) a pharmaceutically acceptable salt thereof; iii) a pharmaceutically acceptable ester thereof; iv) and a pharmaceutically acceptable solvate thereof.
  • Also described is a method of treating a seizure disorder in an animal comprising administering to an animal afflicted or potentially afflicted with such a disorder one or more of the following: i) a pharmaceutically effective amount of a compound of the present invention; ii) a pharmaceutically acceptable salt thereof; iii) a pharmaceutically acceptable ester thereof; iv) and a pharmaceutically acceptable solvate thereof.
  • This invention includes all tautomers, salts, and stereoisomeric forms of compounds of the present invention. This invention also includes all compounds of this invention where one or more atoms are replaced by a radioactive isotope thereof.
  • R5 is C 1 -C 6 alkyl, (CHR6)wC3-C6 cycloalkyl, (CHR6)wCH2C3-C6 cycloalkyl, or CH2(CHR6)wC3-C6 cycloalkyl.
  • R5 is C5-C6 alkyl, (CH2)wC5-C6 cycloalkyl, or (CHR6)wCH2C5-C6 cycloalkyl.
  • R5 is C5-C6 alkyl, optionally substituted with one or two OH groups.
  • R 1 is phenyl, substituted with halogen, cyano, CF 3 , or methoxy
  • R 2 is H or methyl
  • R 5 is C 5 -C 6 alkyl or CH 2 -C 3 -C 6 cycloalkyl.
  • a compound of formula IA, IB, IC, or ID where R 1 is substituted phenyl or unsubstituted phenyl.
  • a compound of formula IA, IB, IC, or ID where R 1 is phenyl, substituted with halogen.
  • R 1 is dihalophenyl or dihalopyridyl
  • R 2 is H
  • R 3 and R 4 are Cl, CF 3 , or CH 3 .
  • R 1 is dihalophenyl or dihalopyridyl
  • R 2 is H
  • R 3 and R 4 are Cl, CF 3 , or CH 3 .
  • R 1 is halophenyl or halopyridyl
  • R 2 is H
  • R 3 and R 4 are CI, CF 3 , or CH 3 .
  • R 5 is C 1 -C 6 alkyl, where the C 1 -C 6 alkyl group is substituted with one or two groups selected, independently, from OH, OMe, OEt, F, CF 3 , Cl, or CN.
  • compound of formula I in which X is S, q is zero, R 1 is substituted phenyl, R 2 is H, and R 5 is C 1 -C 6 alkyl.
  • a compound of formula I in which X is S, q is 1, Y is O, R 1 is substituted phenyl, R 2 is H, and R 5 is C 1 -C 6 alkyl.
  • a compound of formula I in which X is S, q is 1, Y is S, R 1 is substituted phenyl, R 2 is H, and R 5 is C 1 -C 6 alkyl.
  • alkyl substitution at both the 2- and 6-positions of the central benzene ring confers desirable properties, including both increased potency and increased stability in vivo.
  • 2,6-dimethyl substitution is a critical feature of the embodiments of this invention.
  • substitution with alkoxide groups at both the 2- and 6-positions of the central benzene ring also confers a number of desirable properties, including both increased potency and increased stability in vivo.
  • substitution at the 2- and 6-positions of the central benzene ring with substituents chosen from halogen, trifluoromethyl, and methoxy also confers a number of desirable properties, including both increased potency and increased stability in vivo .
  • the most active compounds display a 40- to 400-fold improvement over retigabine, with the most promising compounds displaying EC 50 s in the single-digit nanomolar range. Activities of several compounds of this invention are shown in Table 1 below. The activity of retigabine is shown for comparative purposes.
  • potassium channel modulator refers to a compound capable of causing an increase in potassium channel currents. It also refers to a compound capable of increasing the KCNQ2/3 channel open probability.
  • the inventors have employed the rubidium ion efflux test described below.
  • compounds of the present invention are designed for oral or intravenous dosing of up to approximately 2000 mg per day.
  • this invention contemplates solutions and suspensions of compounds of formula I formulated for intravenous administration.
  • solutions and suspensions comprising a syrup such as sorbitol or propylene glycol, among many other examples, in addition to compounds of the present invention, suitable for oral pediatric administration, are also contemplated.
  • both chewable and non-chewable tablets comprising compounds of the present invention, along with pharmaceutically acceptable tabletting agents and other pharmaceutically acceptable carriers and excipients, are also contemplated.
  • the term "pharmaceutically acceptable carrier” comprises such excipients, binders, lubricants, tabletting agents and disintegrants as are typically used in the art of formulation of pharmaceuticals.
  • examples of such agents include - but are not limited to - microcrystalline cellulose, lactose, starch, and dicalcium phosphate, and Providone.
  • this invention does not contemplate compositions in which active ingredients with primary amine groups are combined with lactose.
  • disintegrants such as sodium starch glycolate, lubricants such as stearic acid and SiO 2 , and solubility enhancers such as cyclodextrins, among many other examples for each group, are contemplated.
  • disintegrants such as sodium starch glycolate, lubricants such as stearic acid and SiO 2 , and solubility enhancers such as cyclodextrins, among many other examples for each group.
  • solubility enhancers such as cyclodextrins
  • the invention also contemplates pharmaceutical formulations for administration to animals, comprising a therapeutically effective amount of a compound of formula I and a veterinary acceptable carrier. Any animal that is susceptible to seizure disorders is included within the scope of this invention.
  • Method A A mixture of 4,6-dimethyl-1H-indole-2-carboxylic acid (3.61g, 19.09 mmol, 1 equiv), copper powder (850 mg, 13.36 mmol, 0.7 equiv), and freshly distilled quinoline (50 mL) were brought at reflux for 2 h. The mixture was then cooled and filtered on Celite. The filtrate was poured on ice, and the solution was brought to pH 4 with concentrated HCl and extracted with ethyl acetate (3x100 ml). The combined extracts were washed with 2 N HCl (3x100 mL), saturated NaHCO 3 , and brine. The organic solution was dried over MgSO 4 and concentrated.
  • 4,6-Dimethylindole (1.08 g) was dissolved in acetic acid (20 ml), and sodium cyanoborohydride (2.3 g) was added portionwise at 15° C. The mixture was stirred at said temperature for one hour and poured into ice water. Saturated aqueous sodium bicarbonate was added to neutralize the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in benzene, and acetic anhydride (840 mg) was added, which was followed by stirring at room temperature for one hour.
  • PC-12 cells were grown at 37 °C and 5 % CO 2 in DMEM/F12 Medium supplemented with 10 % horse serum, 5 % fetal bovine serum, 2 mM glutamine, 100 U/ml penicillin, 100 U/ml streptomycin. They were plated in poly-D-lysine-coated 96-well cell culture microplates at a density of 40,000 cells/well and differentiated with 100 ng/ml NGF-7s for 2-5 days.
  • the medium was aspirated and the cells were washed once with 0.2 ml in wash buffer (25 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM MgCl 2 , 0.8 mM NaH 2 PO 4 , 2 mM CaCl 2 ).
  • the cells were then loaded with 0.2 ml Rb + loading buffer (wash buffer plus 5.4 mM RbCl 2 , 5 mM glucose) and incubated at 37 °C for 2 h. Attached cells were quickly washed three times with buffer (same as Rb + loading buffer, but containing 5.4 mM KCl instead of RbCl) to remove extracellular Rb + .
  • 0.2 ml of depolarization buffer (wash buffer plus 15 mM KCl) with or without compounds was added to the cells to activate efflux of potassium ion channels. After incubation for 10 min at room temperature, the supernatant was carefully removed and collected. Cells were lysed by the addition of 0.2 ml of lysis buffer (depolarization buffer plus 0.1 % Triton X-100) and the cell lysates were also collected. If collected samples were not immediately analyzed for Rb + contents by atomic absorption spectroscopy (see below), they were stored at 4 °C without any negative effects on subsequent Rb + analysis.
  • the concentration of Rb + in the supernatants (Rb + Sup ) and cell lysates (Rb + Lys ) was quantified using an ICR8000 flame atomic absorption spectrometer (Aurora Biomed Inc., Vancouver, B.C.) under conditions defined by the manufacturer.
  • ICR8000 flame atomic absorption spectrometer Aurora Biomed Inc., Vancouver, B.C.
  • One 0.05 ml samples were processed automatically from microtiter plates by dilution with an equal volume of Rb + sample analysis buffer and injection into an air-acetylene flame.
  • the amount of Rb + in the sample was measured by absorption at 780 nm using a hollow cathode lamp as light source and a PMT detector.
  • a calibration curve covering the range 0-5 mg/L Rb + in sample analysis buffer was generated with each set of plates.
  • the effect (E) and compound concentration relationship was plotted to calculate an EC 50 value, a compound's concentration for 50% of maximal Rb + efflux. The results are shown below.

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EP08827266.1A 2007-08-13 2008-08-12 Derivatives of 5-amino-4, 6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators Not-in-force EP2190534B1 (en)

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PL08827266T PL2190534T3 (pl) 2007-08-13 2008-08-12 Pochodne 5-amino-4,6-dipodstawionego indolu i 5-amino-4,6-dipodstawionej indoliny jako modulatory kanału potasowego

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US96452607P 2007-08-13 2007-08-13
US12/189,709 US7786146B2 (en) 2007-08-13 2008-08-11 Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators
PCT/US2008/072926 WO2009023677A1 (en) 2007-08-13 2008-08-12 Derivatives of 5-amino-4, 6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators

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EP2190534A1 EP2190534A1 (en) 2010-06-02
EP2190534B1 true EP2190534B1 (en) 2015-02-18

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EP (1) EP2190534B1 (es)
JP (1) JP2010536771A (es)
KR (1) KR20100075436A (es)
CN (1) CN101795727A (es)
AU (1) AU2008286919B2 (es)
BR (1) BRPI0815210A2 (es)
CA (1) CA2696012C (es)
ES (1) ES2531335T3 (es)
HU (1) HUE025928T2 (es)
MX (1) MX2010001712A (es)
PL (1) PL2190534T3 (es)
RU (1) RU2483060C2 (es)
SG (1) SG183725A1 (es)
TW (1) TW200927096A (es)
WO (1) WO2009023677A1 (es)

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US8722929B2 (en) * 2006-10-10 2014-05-13 Valeant Pharmaceuticals International N-[2-amino-4-(phenylmethoxy)phenyl] amides and related compounds as potassium channel modulators
US8563566B2 (en) * 2007-08-01 2013-10-22 Valeant Pharmaceuticals International Naphthyridine derivatives as potassium channel modulators
US7786146B2 (en) * 2007-08-13 2010-08-31 Valeant Pharmaceuticals International Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators
CN102241608A (zh) * 2011-05-12 2011-11-16 天津市汉康医药生物技术有限公司 瑞替加滨化合物及其组合物
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CN103508960B (zh) * 2012-06-29 2017-12-12 江苏先声药业有限公司 苯并杂环衍生物
CN107098844B (zh) * 2017-05-17 2019-07-30 许昌学院 一种c-5位硝基取代的酰基吲哚啉类化合物的合成方法
CN112010808B (zh) * 2019-05-31 2021-11-30 上海挚盟医药科技有限公司 作为钾通道调节剂的四氢-1h-苯氮杂卓类化合物及其制备和应用
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US8211918B2 (en) 2012-07-03
AU2008286919A1 (en) 2009-02-19
ES2531335T3 (es) 2015-03-13
RU2010109388A (ru) 2011-09-20
US7786146B2 (en) 2010-08-31
BRPI0815210A2 (pt) 2015-03-31
MX2010001712A (es) 2010-07-28
CA2696012A1 (en) 2009-02-19
CN101795727A (zh) 2010-08-04
AU2008286919B2 (en) 2014-05-29
KR20100075436A (ko) 2010-07-02
JP2010536771A (ja) 2010-12-02
US20110118318A1 (en) 2011-05-19
EP2190534A1 (en) 2010-06-02
SG183725A1 (en) 2012-09-27
US20090137635A1 (en) 2009-05-28
CA2696012C (en) 2017-10-31
WO2009023677A1 (en) 2009-02-19
RU2483060C2 (ru) 2013-05-27
TW200927096A (en) 2009-07-01
HUE025928T2 (en) 2016-05-30

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